Analytical Validation of Whole Genome Sequencing in the NICU

Analytical validation to determine performance of a whole genome sequencing test and implications of testing in the NICU environment

Approximately 3.5 million babies are born each year in the United States, with over 400,000 of these infants admitted to the NICU.1,2 Underlying genetic etiologies occur in approximately 1/3 of these babies, and in the past, diagnoses were most often made post-mortem. Regardless, infants with genetic disorders or congenital malformations indicating a possible genetic syndrome not only comprise a substantial proportion of NICU admissions, but disproportionately contribute to neonatal mortality, responsible for about 30–50% of neonatal and infant deaths.

Identifying the underlying etiology quickly for these critically ill infants and children can lead to life-saving treatment, information for the family about what to expect, or the initiation of palliative care. Whole Genome Sequencing (WGS) is a comprehensive genetic test that uses state-of-the-art technology to analyze 98% of a person’s genome using a single NGS assay and is now recommended as a first tier test for children with congenital anomalies, developmental delay, or intellectual disability by the American College of Medical Genetics and Genomics (ACMG).

Prior to WGS, a step-wise approach to testing was required for individuals with rare disease, congenital anomalies, or developmental delay/intellectual disability including multiple tests such as chromosome microarray (CMA), NGS panels, and whole exome sequencing (WES), which is time-consuming and often delays diagnosis and thus medical management or treatment. WGS has a higher diagnostic yield and allows for a comprehensive analysis at a fast turn-around time to provide an accurate diagnosis much earlier than the traditional stepwise approach.

The WGS test sequences every nucleotide in the human genome of an individual to a depth of coverage necessary to build a highly accurate consensus sequence. This consensus sequence is then compared to normal reference sequences and the results are interpreted by board-certified laboratory directors and clinicians. Knowledge of the underlying genetic cause for an individual’s symptoms can be used to determine diagnosis, prognosis, guidetreatment, plan surveillance, and take preventative action. This is a retrospective analytical validation study to determine the performance of this WGS assay.

METHODS

A series of studies were performed to validate and refine a WGS test to determine the performance and clinical application of this diagnostic test. The WGS workflow is validated for various postnatal sample types (blood, buccal swab, saliva, cultured cell lines, purified DNA).

Read more of the white paper here: https://bit.ly/3QzvvBP